Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 316, Issue 3, Pages E410-E417Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00035.2018
Keywords
diabetes; EPRAP; gluconeogenesis; hyperglycemia; insulin sensitivity
Categories
Funding
- Japan Society for the Promotion of Science [26460338, 17K08592, 15K08230]
- Suzuken Memorial Foundation
- Metabolic Syndrome Research Forum Fund
- Takeda Science Foundation
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [17K08592, 15K08230] Funding Source: KAKEN
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Prostaglandin E-2 receptor 4-associated protein (EPRAP) is a key molecule in suppressing inflammatory responses in macrophages. EPRAP is expressed not only in macrophages but also in hepatocytes; however, the role of EPRAP in hepatocytes has not yet been defined. To examine the physiological role of hepatic EPRAP in mice, we performed the glucose tolerance test and the hyperinsulinemic-euglycemic clamp in high-fat sucrose diet (HFSD)-fed wild-type (WT) and Eprap null mice. We evaluated the contribution of EPRAP to gluconeogenesis by pyruvate tolerance test and primary hepatocyte experiments. Furthermore, lentivirus-expressing Eprap-specific small-hairpin RNA was injected in db/db mice. HFSD-fed Eprap null mice had significantly lower blood glucose levels than IIFSD-fed WT mice. Eprap null mice also had low glucose levels after fasting or pyruvic acid injection. Moreover, primary hepatocytes from Eprap-deficient mice showed decreased glucose production and lower expression of the Phosphoe-nolpymate carboxykinase and Glucose 6-phosphatase genes. Lentivirus-mediated hepatic Eprap suppression decreased glucose levels and the expression of gluconeogenic genes in db/db mice. We conclude that EPRAP regulates gluconeogenesis in hepatocytes and is associated with hyperglycemia in diabetic mice. Our data suggest that suppression of EPRAP could be a novel strategy for the treatment of diabetes.
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